PROJECT SUMMARY Allogeneic hematopoietic cell transplantation (HCT) can cure many hematologic cancers and other life- threatening hematologic diseases, but 20-50% of survivors develop chronic graft-versus-host disease (cGVHD), the leading cause of morbidity and mortality in transplant survivors. In cGVHD, the donor's immune cells attack the patient setting up a cascade of events resulting in a pleomorphic multi-organ syndrome reminiscent of autoimmune diseases such as systemic sclerosis, systemic lupus erythematosus, Sjogren's syndrome, and lichen planus. Chronic GVHD is associated with poor quality of life, impaired functional status, and need for prolonged treatment with potent immunosuppressive agents. There are many competing hypotheses about the etiology of human cGVHD with data supporting involvement of T and B cells, macrophages, dendritic cells, fibroblasts and endothelial cells. Cytokines, chemokines and other proteins have been implicated. To our knowledge, the microbiome has not been investigated in cGVHD patients. This project will address key gaps in our understanding of human cGVHD development: what are the early events that occur in the skin, eyes, mouth, and blood before cGVHD clinical onset? Do early changes in local tissues mirror changes in the rest of the body, and do they reflect the pathophysiology of cGVHD? Can we detect subclinical cGVHD using new testing strategies, potentially allowing the opportunity for targeted pre-emptive treatment? To address these questions, we will enroll 100 evaluable patients (80 at Fred Hutchinson, 20 at the National Cancer Institute) in a prospective, longitudinal study involving intensive bimonthly assessments. Entitled the ?CATCH? study (Close Assessment and Testing for Chronic GVHD), this unique cohort will allow us to ?watch? cGVHD as it develops in humans. No other situation in medicine except solid organ transplantation provides a similar window into the evolution of an alloimmune response, and findings could be relevant to many other auto- and alloimmune phenomenon. Participants will be studied before transplant, then at bimonthly intervals through the first post-transplant year starting at month 3. Assessments include physical exams, symptom measurement, and sampling of blood, conjunctival washings, saliva, and feces. Participants will undergo skin and oral biopsies at 2-3 timepoints and also have optical coherence tomography and other specialized imaging of the skin, eyes, and mouth every other month. Biologic analyses of cytokines, chemokines, microbiome and cellular subsets will be performed on informative samples to test prior observations in the murine and human systems and to generate new hypotheses. Completion of this project will advance our understanding of the biologic underpinnings of human cGVHD and guide therapeutic approaches based on a comprehensive understanding of systemic and tissue-specific pathophysiology, in order to decrease the morbidity and mortality of this common transplant complication.